Natural Cancer Agent?,

Unraveling Protein Reveals Mechanics of Natural Anti-Cancer Agent

Human tissues are made up of specialized cells held together by a fabric of proteins, which form knots in a kind of stretchable "glue." As a tissue is stretched, the protein knots between cells unravel, making the net mysteriously stronger by building new meshes. One such protein glue, fibronectin III-1, has been known to play an important role in this process, but its actual structure and behavior has remained elusive. Stretching of fibronectin III-1, which occurs naturally in tissues, renders the protein extremely adhesive, strengthening the "glue" between cells, thereby assisting in wound healing and preventing metastasis.

In a collaboration led by the Theoretical and Computational Biophysics Group (TCBG) at the University of Illinois, researchers have used NMR structural analysis and computer modeling to establish the molecular structure and mechanical strength of fibronectin III-1 (PNAS USA, 100:14784-14789, 2003). The researchers first predicted the protein's structure computationally, then verified and improved on the prediction using the so-called 2D NMR spectra of the protein that explores the nuclear Overhauser effect, well-known in the field of nuclear spin physics. "The structure revealed that fibronectin III-1, along with the other fibronectins found between cells, is made up of two sheets stacked together like a sandwich," said Professor Klaus Schulten, holder of a Swanlund Chair in Physics and director of the TCBG at the Beckman Institute for Advanced Science and Technology. "However, in the case of fibronectin III-1, a weak sheet covers a strong sheet, like a small bun covering a large bun."

Simulations, stretching the protein as it happens in tissue, readily unraveled the weak sheet, but required a longer time to unravel the strong sheet. Physics graduate student Mu Gao, a key member of the collaboration, has created a movie (2.2 MB) of the stretching of fibronectin III-1 that dramatically demonstrates this behavior, i.e. that natural stretching exposes the fibronectin-III-1 strong sheet.

Other researchers have shown independently that the strong sheet is also the main component of the molecule anastellin, which strengthens fibronectin fibers between cells and acts as an anticancer agent by preventing metastasis in some cancers.

Other collaborators are Viola Vogel (Center for NanoTechnology, University of Washington, Seattle), David Craig (former graduate student in bioengineering at U. Washington), Olivier Lequin (University Pierre and Marie Curie, Paris), and Iain D. Campbell (University of Oxford, U.K.). Further information about this fascinating work is available from Mechanical Proteins or Mu Gao.

The National Institutes of Health, the National Science Foundation, Federation of European Biochemical Societies, and University of Washington Initiative Fund supported the work. The conclusions presented are those of the researchers, and not necessarily those of the funding agencies.